Submissions for variant NM_000059.4(BRCA2):c.7033C>G (p.Gln2345Glu)

dbSNP: rs886040685

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579918	SCV000683845	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 2345 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not impact drug sensitivity or cell viability in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in an individual affected with ovarian cancer (PMID: 28692638) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_006914). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805741	SCV000945709	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 2345 of the BRCA2 protein (p.Gln2345Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 28692638). ClinVar contains an entry for this variant (Variation ID: 489777). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
MGZ Medical Genetics Center	RCV002289850	SCV002579454	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
Ambry Genetics	RCV000579918	SCV002666606	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	The p.Q2345E variant (also known as c.7033C>G), located in coding exon 13 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7033. The glutamine at codon 2345 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was identified in a cohort of 826 unselected Chinese ovarian cancer patients (Wu X et al. Int J Gynecol Cancer, 2017 Oct;27:1650-1657). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004001245	SCV004844351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 2345 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not impact drug sensitivity or cell viability in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in an individual affected with ovarian cancer (PMID: 28692638) and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_006914). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000340	SCV005625265	uncertain significance	not provided	2024-01-23	criteria provided, single submitter	clinical testing	The BRCA2 c.7033C>G (p.Gln2345Glu) variant has been reported in the published literature in in an individual with ovarian cancer (PMID: 28692638 (2017)). This variant has identified in reportedly healthy individuals (PMID: 32467295 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.